ASH: Bendamustine and Toxicity

We're going back to the ASH conference, looking a little deeper into one of the presentations that delivered some good news. The session discussed results of the GALLIUM study, which showed that in some situations, Obinutuzumab (an anti-CD20 monoclonal antibody) worked better that Rituxan.

However, the data from the study also delivered some bad news -- about Bendamustine. It wasn't the focus of the ASH session, but it got some people talking, and made them very surprised.

I've been hesitating to write about this for a couple of weeks until I worked through it, but now I have and I'm ready to write. But because Bendamustine is a popular treatment for Follicular Lymphoma, I'm asking you to PLEASE read all the way through. I think the best discussion of the bad news about Bendamustine comes from the article "Bendamustine Toxicity in FL Raises Eyebrows -- and Questions" from Medscape Medical News. Read all of that article as well. (You might need a password to get in, but the account is free.)

So here's the deal:

In the GALLIUM study reported at ASH, 1202 patients were given either Rituxan + chemo, followed by Rituxan maintenance, or Obinutuzumab + chemo, followed by Obinutuzumab maintenance. Overall, the study found that patients in the Obinutuzumab arm had a higher Progression-Free Survival -- significantly higher. One of the big problems with Obinutuzumab was that it had higher toxicity that Rituxan, so patients had more side effects and more problems overall, in addition to having a longer PFS.

But then they broke things down a different way, looking at the different chemotherapies that were combined with Obinutuzumab and Rituxan. They found that of the three, patients who took Bendamustine with either O or R had a higher instance of death that with the other chemotherapies (CHOP or CVP).

This is what "raised eyebrows" at ASH -- a treatment that has been very popular in the last few years has an increased death rate over other options. Researchers reported 19 deaths for patients taking Obinutuzumab + Bendamustine (about 5.6% of that group in the study), and 15 deaths for patients taking R + Bendamustine (4.4%). For those taking CHOP or CVP, only 9 deaths occurred.

 Definitely not what we want to hear. HOWEVER, this is why that Medscape Medical News article is so good -- they interview some very smart people who have lots of experience with Bendamustine, to get an explanation and to find out how this new data will affect the way they treat patients.

In a nutshell, it doesn't change things in a really drastic way. The experts interviewed will either continue using Bendamustine the way they have been using it, and/or will be more careful about how they use it.

For example, one of the experts interviewed is Dr. Bruce Cheson (lots of you know how much I respect Dr. Cheson and his work). Here's what he has to say about the study:

"I was quite surprised by the toxicity [reported for the bendamustine arms in the GALLIUM study]. It has not been my experience," Bruce D. Cheson, MD, professor of medicine, head of hematology and deputy chief of hematology-oncology at the Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, told Medscape Medical News.

Dr Cheson uses bendamustine for most patients with previously untreated FL. Although the data from the GALLIUM study are compelling and support use of obinutuzumab because of the advantage in PFS, its efficacy is counterbalanced by a higher level of toxicity, he noted.

"There may be a select patient population, such as the younger, fit patient, in whom I may use G-bendamustine in preference to R-bendamustine," Dr Cheson said. "However, for most, R-bendamustine remains my standard," he said.

For patients in whom there is a suspicion of occult transformation, Dr Cheson uses R-CHOP as induction in preference to R-bendamustine.

Some things worth noting here: In his experience, Dr. Cheson has not seen this kind of problem with Bendamustine. I think that's important. A clinical trial like the GALLIUM trial provides important, controlled data to help us understand how a treatment works in a large group. But it also controls the circumstances under which it is used. In this case, the GALLIUM study uses Bendamustine with a monoclonal antibody, and THEN follows that up with 6 months of maintenance.

At least one expert thinks that it is the maintenance that might create the problem. Bendamustine suppresses the immune system, and when you follow that up with an antibody that kills immune cells, it makes sense that there is a greater chance for infections. (Although not all of the deaths occurred because of infections.)

So some of the experts interviewed won't change the way they do things, and will keep giving patients R-Bendamustine, but perhaps without maintenance. Others will focus more closely on the individual patient, and what his or her body might be able to handle. Some may use CHOP or CVP if they plan to use maintenance, while others may use O + Bendamustine for the initial treatment,but then Rituxan for maintenance.

For me, I'm getting two big lessons from this.

First, Bendamustine is still on the table. My old oncologist, Dr. R, had always said that Bendamustine was going to be a consideration if and when I needed treatment again. This hasn't scared me off. I trust the experts that were interviewed, and none of them announced that they were giving up on Bendamustine, only that they were going to ask more questions about it.

Second, I think this will slow things down. As one of the experts noted, Bendamustine was pretty quickly adopted as a preference over CHOP, based on one particular study. Other studies backed up its effectiveness and safety. But maybe there needs to be more nuanced examination of who will benefit from the treatment. Maybe this will slow things down a little, and force patients (like me) from being so enthusiastic about it. That doesn't mean I wouldn't take it -- it just means I need to have a longer conversation with my oncologist about whether it's right for me, given whatever circumstances lead me to need treatment.

I'm sorry I couldn't start the New Year of with something more positive. It seems like everyone I know is looking for something to be positive about in 2017. But if nothing else, this is a good reminder -- and a good time for it -- that we should be active patients who take as much control of our own treatment as we can, asking questions and demanding answers, and not accepting what we hear about or read about online (including this blog).

Stay healthy everyone, and have a great New Year.